Supplemental iron exacerbates aminoglycoside ototoxicity in vivo.
There is increasing evidence to suggest that free radical generation is central to a variety of pathological processes, including drug toxicity. Studies demonstrating the ability of gentamicin to facilitate the generation of radical species suggest that this process plays an important role in aminoglycoside-induced ototoxicity. Because transition metals, particularly iron, play an important role in the production of free radicals and the generation of reactive oxygen species, we sought to determine whether gentamicin-induced ototoxicity is exacerbated by increases in serum iron levels. To this end, we assessed the effects of supplemental iron administration (2 mg/kg/day and 6 mg/kg/day) on changes in auditory function induced by co-administration of gentamicin (100 mg/kg/day for 30 days). Experiments were carried out on pigmented guinea pigs initially weighing 250-300 g. Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds, estimated every third day throughout the treatment period by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results showed that animals receiving iron in combination with gentamicin demonstrated a more rapid and profound elevation in CAP thresholds compared with animals receiving gentamicin alone. This effect occurred in a dose-dependent manner. Animals receiving supplemental iron alone maintained normal CAP thresholds throughout the treatment period. There was no statistically significant difference in serum gentamicin levels between groups receiving gentamicin alone or gentamicin plus iron. These results provide further evidence of the recently reported intrinsic role of iron in aminoglycoside ototoxicity, and highlight a potential risk of aminoglycoside administration in patients with elevated serum iron.
Conlon
B J
BJ
Division of Otolaryngology-Head and Neck Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Smith
D W
DW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D001309:Auditory Threshold / Q000187:drug effects; D003051:Cochlea / Q000187:drug effects* / Q000473:pathology; D003638:Deafness / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005839:Gentamicins / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D006168:Guinea Pigs; D019266:Iron, Dietary / Q000097:blood / Q000494:pharmacology*; D012405:Round Window, Ear / Q000187:drug effects
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D019266:Iron, Dietary